CN111803086B - Three-electrode subcutaneous implantation type glucose sensor and manufacturing method thereof - Google Patents
Three-electrode subcutaneous implantation type glucose sensor and manufacturing method thereof Download PDFInfo
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Abstract
The invention relates to a three-electrode subcutaneous implanted glucose sensor and a manufacturing method thereof, wherein the sensor adopts a three-electrode form of a working electrode, a reference electrode and an auxiliary electrode, a tested micro-current passes through the working electrode and the auxiliary electrode, and the reference electrode basically has no current, so that the service life of the reference electrode is prolonged; by improving the manufacturing process of the sensor electrode, the process is simple, the quality is controllable, the stability of the working electrode glucose oxidase is kept, and the accuracy of the test data of the sensor is ensured; in addition, carriers such as bovine serum albumin and the like are cancelled, the activity and the stability of the glucose oxidase are ensured by adopting a mode of bifunctional coupling of glutaraldehyde and silane, the potential safety hazard to a human body is reduced, and the rejection reaction of the human body is lightened; through the dismantled and assembled block connected mode of transmitter and sensor for sensor and transmitter can conveniently separate, realize changing behind the sensor transmitter and can also used repeatedly, have reduced user's use cost.
Description
Technical Field
The invention relates to the field of needle-shaped sensors for monitoring blood sugar of diabetics in real time, in particular to a three-electrode subcutaneously implanted glucose sensor and a manufacturing method thereof.
Background
The dynamic blood glucose monitoring system (RGMS) is a new type of continuous dynamic blood glucose monitoring system that has been put into clinical use in recent years by attaching one or more probes, like needles, for placement in the subcutaneous tissue. The diameter of the probe is very small, and the patient does not feel pain or discomfort obviously when the probe is placed in the body. The instrument receives an electric signal reflecting the blood sugar change from the probe at a certain time interval, and converts the average value of the electric signals acquired for a plurality of times into the blood sugar value to be stored. Several hundred blood glucose values can be recorded per day. The dynamic blood glucose monitor can also simultaneously store the time of eating, moving, taking medicine and the like. Therefore, the patient can not suffer from acupuncture every day, and the blood glucose monitoring system can provide a daily blood glucose graph, a multi-day blood glucose graph fluctuation trend analysis and a summary of daily blood glucose data, and is a new breakthrough of blood glucose detection.
In order to improve the accuracy of blood glucose monitoring, the detection needle of the dynamic blood glucose monitor, i.e. the electrode, usually needs the working electrode and the reference electrode to be used in cooperation. Publication number CN101530328B discloses a two-electrode subcutaneously implantable glucose sensor with a working electrode and a reference electrode, which improves and optimizes the performance, mutual compatibility and consistency of practical glucose sensors. Although the performance and stability of the sensor are guaranteed to a certain extent, the reference electrode can pass current, and the silver chloride contained in the reference electrode can react with electrons to AgCl + e - →Ag+Cl - So that the silver chloride in the silver/silver chloride layer is continuously consumed, and the service life of the reference electrode is influenced; in addition, the sensor electrode is made of more biochemical materials, too complex in process, not beneficial to the control of the electrode quality, high in rejection rate and higher in sensor cost; in particular, the crosslinking of glucose oxidase requires the use of bovine serum albumin or human serum albumin as a carrier, which has a certain biological safety risk to the human body and increases the possibility of human rejection.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a three-electrode subcutaneous implanted glucose sensor and a manufacturing method thereof, the three-electrode subcutaneous implanted glucose sensor adopts a three-electrode form of a working electrode, a reference electrode and an auxiliary electrode, a tested micro-current passes through the working electrode and the auxiliary electrode, the reference electrode only measures voltage, and basically no current passes through, so that the service life of the reference electrode is prolonged, namely the service life of the sensor is prolonged, and the three-electrode subcutaneous implanted glucose sensor can be implanted and worn for a plurality of days from the original state to half a month to one month; through the improvement of the manufacturing process of the sensor electrode and the simplification of biochemical materials, the complex process becomes simple and the quality is controllable, the cost of the sensor is reduced, the stability of the glucose oxidase of the working electrode is kept through the process improvement, and the accuracy of the test data of the sensor is ensured; in addition, a carrier of glucose oxidase such as bovine serum albumin or human serum albumin is cancelled, the activity and stability of the glucose oxidase are ensured by adopting a mode of coupling double functions of glutaraldehyde and silane, the potential biochemical safety hazard to a human body is reduced, and the rejection reaction of the human body is lightened; through the dismantled and assembled block connected mode of transmitter and sensor for sensor and transmitter can conveniently separate, realize changing behind the sensor transmitter and can also used repeatedly, have reduced user's use cost.
The specific technical scheme of the invention is as follows: a three-electrode subcutaneous implantation type glucose sensor comprises a needle-shaped working electrode, a reference electrode and an auxiliary electrode, wherein the working electrode, the reference electrode and the auxiliary electrode are fixed on a sensor seat;
the working electrode comprises a first conductive substrate, a first metal transition layer, a first noble metal layer, an inner coupling layer, an immobilized enzyme layer, an outer coupling layer and a first polymer film layer from inside to outside;
the reference electrode comprises a second conductive substrate, a second metal transition layer, a silver/silver chloride layer and a second polymer film layer from inside to outside;
the auxiliary electrode comprises a third conductive substrate, a third metal transition layer, a second noble metal layer, a coupling layer and a third polymer film layer from inside to outside.
The sensor used for continuous blood sugar monitoring of the diabetic patient is a consumable product and needs to be replaced regularly, the most key factor influencing the service life of the sensor is the loss of a reference electrode, and when electrons pass through the reference electrode, the silver chloride contained in the reference electrode reacts with the electrons to generate AgCl + e - →Ag+Cl - The silver chloride in the silver/silver chloride layer is continuously consumed to influence the service life of the reference electrode, and most of electrons can pass through the auxiliary electrode by adding the auxiliary electrode, so that the consumption of the silver/silver chloride layer is reduced, and the service life of the sensor is prolonged; the working electrode is an electrode which plays a main electrochemical reaction, a biological enzyme which reacts with human blood glucose is present in the working electrode, namely the immobilized enzyme layer, the first polymer film layer which limits the reaction amount of the glucose and the biological enzyme is arranged on the outer layer, in order to improve the stability of the biological enzyme and maintain the activity, the immobilized enzyme layer is usually fixed on a carrier, and a coupling agent is adopted to carry out coupling between the immobilized enzyme layer and the first polymer film layerAnd the carrier usually adopts bovine serum albumin or human serum albumin, so that certain biological safety hazard exists to a human body.
Preferably, the sensor seat comprises a plastic substrate, three metal connection points which are arranged in a triangular shape and are positioned in the middle of the plastic substrate, a mounting hole is formed in the middle of each metal connection point, and the tail ends of the working electrode, the reference electrode and the auxiliary electrode respectively penetrate through the mounting holes and then are connected and conducted with the metal connection points.
The working electrode, the reference electrode and the auxiliary electrode are arranged on the plastic substrate in a triangular shape, so that the distance among the three electrodes is short, and the monitoring value of blood sugar is more accurate.
Preferably, the three metal connecting points are arranged in a regular triangle, and the side length of the regular triangle is 3mm to 6mm.
When the distance between the working electrode, the reference electrode and the auxiliary electrode is too close, the resistance of the implanted human body is large, and when the distance is too far, the data deviation of blood glucose monitoring is large, so that the implanted human body can be smoothly implanted when the distance is from 3mm to 6mm, and the data accuracy of the sensor can be ensured.
Preferably, the working electrode, the reference electrode and the auxiliary electrode are all mounted perpendicular to the plastic substrate.
The working electrode, the reference electrode and the auxiliary electrode are implanted into the human body vertically and smoothly, and particularly when an auxiliary wearing tool is used, the vertical implantation is very easy, the human body basically does not have pain, after the vertical implantation, the plastic substrate and the implanted surface of the human body are well attached, and the stability of the implanted sensor can be ensured.
Preferably, the sensor holder further comprises at least three metal contacts on the plastic substrate, the metal contacts are respectively conducted with the metal connection points, and the plastic substrate is provided with a clamping mechanism connected with the emitter.
The emitter provides voltage required by working for the sensor and receives current generated by the sensor electrode, the metal contact is opposite to the contact on the emitter, and when the emitter is clamped and connected with the sensor seat, the metal contact is conducted with the contact on the emitter to realize transmission of current data; the sensor is the consumer, needs the periodic replacement, the transmitter can be used for a long time, through block mechanism can make things convenient for the sensor with the separation of transmitter realizes the used repeatedly of transmitter.
Preferably, an operational amplifier is installed in the transmitter, the reference electrode is electrically connected to an inverting input terminal of the operational amplifier through the metal connection point and the metal contact, and the auxiliary electrode is electrically connected to an output terminal of the operational amplifier through the metal connection point and the metal contact.
The reference electrode is connected with the inverted input end of the operational amplifier, the auxiliary electrode is connected with the output end of the operational amplifier, so that most of current passes through the auxiliary electrode, almost no current flows through the reference electrode, namely no electrons pass through the reference electrode, and the AgCl + e reaction is weakened - →Ag+Cl - The service life of the reference electrode is prolonged.
Preferably, the first conductive base material is stainless steel, the first metal transition layer is gold, the first noble metal layer is platinum, the inner coupling layer and the outer coupling layer are silane, the immobilized enzyme layer is glucose oxidase, and the first polymer membrane layer is polyurethane and/or polyethylene glycol.
The first conductive base is preferably made of 304 stainless steel or 316 stainless steel, so that the toughness is good, the human rejection reaction is small, and the safety is high; the immobilized enzyme layer is glucose oxidase which can effectively catalyze glucose + O 2 → gluconic acid + H 2 O 2 The first polymer film layer is made of polyurethane and/or polyethylene glycol, glucose can be limited from entering the immobilized enzyme layer to participate in the reaction, and sufficient oxygen is guaranteed to participate in the reaction, so that the concentration of the glucose is H 2 O 2 Generate blocks of quantitiesDetermining a factor; the first metal transition layer is made of gold, and the first noble metal layer is made of platinum and can effectively catalyze H 2 O 2 →O 2 +2H + +2e - Reaction takes place with H 2 O 2 The generated quantity is converted into an electron generated quantity, electrons pass through the working electrode to generate micro current, and the gold and the platinum can reduce the signal to noise ratio so that the micro current and the glucose concentration are in a linear positive correlation; the inner coupling layer and the outer coupling layer are preferably selected from silane, so that a good coupling effect can be achieved, the stability of the immobilized enzyme layer is improved, the process is simplified, and the quality of the working electrode is controllable.
Preferably, the second conductive base material is stainless steel, the second metal transition layer is silver, and the second polymer film layer is polyurethane and/or polyethylene glycol.
The second conductive substrate is preferably made of 304 stainless steel or 316 stainless steel, so that the toughness is good, the human rejection reaction is small, and the safety is high; the second metal transition layer is silver, and the silver/silver chloride layer is transited outside the silver layer, so that the accuracy and the stability are high.
Preferably, the third conductive base material is stainless steel, the third metal transition layer is gold, the second noble metal layer is platinum, the coupling layer is silane, and the third polymer film layer is polyurethane and/or polyethylene glycol.
The third conductive substrate is preferably made of 304 stainless steel or 316 stainless steel, so that the toughness is good, the human rejection reaction is small, and the safety is high; the third metal transition layer is made of gold, and the second noble metal layer is made of platinum, so that the current signal-to-noise ratio can be reduced, and the current stability after the third metal transition layer and the working electrode form a loop is ensured.
The invention also discloses a manufacturing method of the three-electrode subcutaneous implanted glucose sensor, which comprises the following steps:
the sensor comprises a needle-shaped working electrode, a reference electrode and an auxiliary electrode, wherein the working electrode, the reference electrode and the auxiliary electrode are fixed on a sensor seat;
the working electrode comprises a first conductive base body, a first metal transition layer, a first noble metal layer, an inner coupling layer, an immobilized enzyme layer, an outer coupling layer and a first high polymer film layer from inside to outside, wherein the first conductive base body is made of stainless steel, the first metal transition layer is made of gold, the first noble metal layer is made of platinum, the inner coupling layer and the outer coupling layer are made of silane, the immobilized enzyme layer is glucose oxidase, and the first high polymer film layer is made of polyurethane and/or polyethylene glycol;
the reference electrode comprises a second conductive substrate, a second metal transition layer, a silver/silver chloride layer and a second polymer film layer from inside to outside, wherein the second conductive substrate is made of stainless steel, the second metal transition layer is made of silver, and the second polymer film layer is made of polyurethane and/or polyethylene glycol;
the auxiliary electrode comprises a third conductive base body, a third metal transition layer, a second noble metal layer, a coupling layer and a third high molecular film layer from inside to outside, wherein the third conductive base body is made of stainless steel, the third metal transition layer is made of gold, the second noble metal layer is made of platinum, the coupling layer is made of silane, and the third high molecular film layer is made of polyurethane and/or polyethylene glycol;
the first metal transition layer of the working electrode is covered on the outer layer of the first conductive matrix by adopting a cation etching method; the first noble metal layer is covered on the outer layer of the first metal transition layer by adopting a cation etching method or an electrochemical deposition method; the inner coupling layer is covered on the outer layer of the first noble metal layer in a dipping or coating mode; the immobilized enzyme layer is attached to the outer layer of the inner coupling layer by an enzyme solution in a dipping or coating mode; the outer coupling layer is covered on the outer layer of the immobilized enzyme layer in a dipping or coating mode; the first polymer film layer is covered on the outer layer of the outer coupling layer in a dipping or coating mode.
The working electrode is characterized in that a gold layer is electroplated on the outer layer of the stainless steel needle, a platinum layer is deposited on the outer layer of the gold layer by a cation etching method or an electrochemical deposition method, silane is soaked or coated on the outer layer of the platinum layer, then glucose oxidase is soaked or coated on the outer layer, silane is soaked or coated on the outer layer of the enzyme layer, and finally polyurethane and/or polyethylene glycol is soaked or coated on the outer layer of the enzyme layer.
Preferably, the second metal transition layer of the reference electrode covers the outer layer of the second conductive substrate by a cation etching method; the silver/silver chloride layer is formed by chlorination of the second metal transition layer; the second polymer film layer is covered on the outer layer of the silver/silver chloride layer in a dipping or coating mode.
The reference electrode is used as the reference electrode and can ensure the voltage stability.
Preferably, the third metal transition layer of the auxiliary electrode covers the outer layer of the third conductive substrate by a cation etching method; the second noble metal layer is covered on the outer layer of the third metal transition layer by adopting a cation etching method or an electrochemical deposition method; the coupling layer is covered on the outer layer of the second noble metal layer in a dipping or coating mode; the third high molecular film layer is covered on the outer layer of the coupling layer in a dipping or coating mode.
The auxiliary electrode is equivalent to the working electrode, the glucose oxidase layer is removed, other structures and manufacturing methods are the same as those of the working electrode, and the stability of current after the auxiliary electrode and the working electrode form a loop is guaranteed.
Preferably, the solute of the enzyme solution is glucose oxidase, the solution is phosphate buffer solution, and the concentration of the glucose oxidase is 0.02-0.2 g/ml.
The glucose oxidase has better activity under the condition that the concentration of the glucose oxidase in the phosphoric acid buffer solution is 0.02 g/ml-0.2 g/ml, and has better effect on the blood sugar catalytic reaction of a human body.
Preferably, the glucose oxidase is cross-linked and solidified by glutaraldehyde.
Mixing glutaraldehyde and glucose oxidase solution in a certain proportion, covering the silane layer by adopting a dipping or coating mode, and dipping or coating the silane layer on the outer layer; free glucose oxidase is coupled through double functions of glutaraldehyde and silane, a sandwich layer similar to a sandwich is formed through crosslinking and curing, and free enzyme is combined into an aggregate, so that active sites of the enzyme are denser, the stability is high, and the stable and durable reaction capability is realized in continuous glucose monitoring.
Preferably, the crosslinking temperature of the glucose oxidase and the glutaraldehyde is 25-35 ℃, and the single crosslinking time is 2-60min.
The glucose oxidase and the glutaraldehyde are crosslinked for 2 to 60min at the temperature of 25 to 35 ℃, so that the enzyme activity is stable, the aggregation is better, and the effect of the blood glucose catalytic reaction of a human body is ensured.
Preferably, the glucose oxidase and the glutaraldehyde are impregnated or coated on the working electrode for not less than 3 times.
Through repeated dipping or coating, the glucose oxidase is more uniformly distributed on the working electrode, the thickness of the immobilized enzyme layer is thicker, the continuous glucose monitoring of a human body is more stable and durable, and the service life of the working electrode is prolonged.
In conclusion, the invention has the following beneficial effects:
1. the three-electrode type sensor is characterized in that a working electrode, a reference electrode and an auxiliary electrode are adopted, the tested micro-current passes through the working electrode and the auxiliary electrode, the reference electrode only measures voltage, and basically no current passes through the reference electrode, so that the service life of the reference electrode is prolonged, namely the service life of the sensor is prolonged, and the sensor is prolonged from being originally implanted and worn for a few days to being implanted and worn for a half month to a month;
2. through the improvement of the manufacturing process of the sensor electrode and the simplification of biochemical materials, the complex process becomes simple and the quality is controllable, the cost of the sensor is reduced, the stability of the glucose oxidase of the working electrode is kept through the process improvement, and the accuracy of the test data of the sensor is ensured;
3. the carrier of glucose oxidase such as bovine serum albumin or human serum albumin is cancelled, the activity and stability of the glucose oxidase are ensured by adopting a mode of coupling double functions of glutaraldehyde and silane, the potential biochemical safety hazard to the human body is reduced, and the rejection reaction of the human body is lightened;
4. through the dismantled and assembled block connected mode of transmitter and sensor for sensor and transmitter can conveniently separate, and the transmitter can also used repeatedly after realizing changing the sensor, has reduced user's use cost.
Drawings
FIG. 1 is a perspective view of a sensor of the present invention with the tip side of the sensor electrode facing up;
FIG. 2 is a perspective view of the sensor of the present invention with the tip of the electrode facing downward;
FIG. 3 is a schematic diagram of the construction of the working electrode of the sensor of the present invention;
FIG. 4 is a schematic diagram of a reference electrode of the sensor of the present invention;
FIG. 5 is a schematic diagram of the structure of the auxiliary electrode of the sensor according to the present invention;
FIG. 6 is a schematic diagram of a reference electrode and an auxiliary electrode of a sensor in conjunction with an operational amplifier according to the present invention;
FIG. 7 is a line graph showing the linear correlation variation of the three-electrode sensor and the two-electrode sensor according to the present invention;
FIG. 8 is a comparative graph of a three electrode sensor reference electrode and a two electrode sensor reference electrode test of the present invention;
in the figure, 1-working electrode, 11-first conductive substrate, 12-first metal transition layer, 13-first noble metal layer, 14-inner coupling layer, 15-immobilized enzyme layer, 16-outer coupling layer, 17-first polymer film layer, 2-reference electrode, 21-second conductive substrate, 22-second metal transition layer, 23-silver/silver chloride layer, 24-second polymer film layer, 3-auxiliary electrode, 31-third conductive substrate, 32-third metal transition layer, 33-second noble metal layer, 34-coupling layer, 35-third polymer film layer, 4-sensor seat, 41-plastic substrate, 411-clamping mechanism, 42-metal connection point and 43-metal contact.
Detailed Description
The invention will be further explained by means of specific embodiments with reference to the drawings.
Example 1: referring to fig. 1, fig. 2, fig. 3, fig. 4 and fig. 5, a three-electrode subcutaneously implantable glucose sensor comprises a needle-shaped working electrode 1, a reference electrode 2 and an auxiliary electrode 3, wherein the working electrode 1, the reference electrode 2 and the auxiliary electrode 3 are fixed on a sensor seat 4;
the working electrode 1 comprises a first conductive substrate 11, a first metal transition layer 12, a first noble metal layer 13, an inner coupling layer 14, an immobilized enzyme layer 15, an outer coupling layer 16 and a first polymer membrane layer 17 from inside to outside;
the reference electrode 2 comprises a second conductive substrate 21, a second metal transition layer 22, a silver/silver chloride layer 23 and a second polymer film layer 24 from inside to outside;
the auxiliary electrode 3 includes, from inside to outside, a third conductive substrate 31, a third metal transition layer 32, a second noble metal layer 33, a coupling layer 34, and a third polymer film layer 35.
The sensor used for continuous blood sugar monitoring of the diabetic patient is a consumable product and needs to be replaced regularly, the most key factor influencing the service life of the sensor is the loss of the reference electrode 2, and when electrons pass through the reference electrode 2, the silver chloride contained in the reference electrode 2 reacts with the electrons to generate AgCl + e - →Ag+Cl - The silver chloride in the silver/silver chloride layer 23 is continuously consumed to influence the service life of the reference electrode 2, and most of electrons can pass through the auxiliary electrode 3 by adding the auxiliary electrode 3, so that the consumption of the silver/silver chloride layer 23 is reduced, and the service life of the sensor is prolonged; the working electrode 1 is an electrode which plays a main electrochemical reaction, a biological enzyme which reacts with the glucose in the blood of a human body, namely an immobilized enzyme layer 15, is arranged in the working electrode, a first polymer film layer 17 which limits the reaction amount of the glucose and the biological enzyme is arranged on the outer layer, in order to improve the stability of the biological enzyme and maintain the activity, the immobilized enzyme layer 15 is usually fixed on a carrier, a coupling agent is adopted to couple the immobilized enzyme layer 15 and the first polymer film layer 17, and the carrier usually uses bovine serum albumin or human serum albumin, so that certain biological safety hazards exist for the human body.
As shown in fig. 1 and 2, the sensor base 4 includes a plastic substrate 41, three metal connection points 42 arranged in a triangle in the middle of the plastic substrate 41, a mounting hole is formed in the middle of each metal connection point 42, and the needle tail ends of the working electrode 1, the reference electrode 2 and the auxiliary electrode 3 respectively penetrate through the mounting holes and then are connected and conducted with the metal connection points 42.
The working electrode 1, the reference electrode 2 and the auxiliary electrode 3 are arranged on the plastic substrate 41 in a triangular shape, so that the distance among the three electrodes is short, and the monitoring value of blood sugar is more accurate.
As shown in FIGS. 1 and 2, the three metal connection points 42 are arranged in a regular triangle, and the side length of the regular triangle is 3mm to 6mm.
When the distance between the working electrode 1, the reference electrode 2 and the auxiliary electrode 3 is too close, the resistance of the implanted human body is large, and when the distance is too far, the data deviation of blood glucose monitoring is large, so that the implanted human body can be smoothly implanted when the distance is from 3mm to 6mm, and the data accuracy of the sensor can be ensured.
As shown in fig. 1, the working electrode 1, the reference electrode 2, and the auxiliary electrode 3 are all mounted perpendicular to the plastic base 41.
The working electrode 1, the reference electrode 2 and the auxiliary electrode 3 are implanted into the human body vertically and smoothly, particularly when an auxiliary wearing tool is used, the vertical implantation is very easy, the human body basically does not feel pain, after the vertical implantation, the plastic substrate 41 and the implanted surface of the human body are well attached, and the stability of the implanted sensor can be ensured.
As shown in fig. 1 and 2, the sensor base 4 further includes at least three metal contacts 43 located on the plastic substrate 41, the metal contacts 43 are respectively conducted with the metal connection points 42, and the plastic substrate 41 is provided with a fastening mechanism 411 connected with the transmitter.
The emitter provides voltage required by work for the sensor and receives current generated by the sensor electrode, the metal contact 43 is opposite to the contact on the emitter, and when the emitter is clamped and connected with the sensor seat 4, the metal contact 43 is conducted with the contact on the emitter to realize the transmission of current data; the sensor is the consumer, needs the periodic replacement, and the transmitter can use for a long time, can make things convenient for the separation of sensor and transmitter through block mechanism 411, realizes the used repeatedly of transmitter.
Example 2: as shown in fig. 6, an operational amplifier is installed in the transmitter, the reference electrode 2 is electrically connected to the inverting input terminal of the operational amplifier through a metal connection point 42 and a metal contact 43, and the auxiliary electrode 3 is electrically connected to the output terminal of the operational amplifier through the metal connection point 42 and the metal contact 43.
The reference electrode 2 is connected with the inverted input end of the operational amplifier, the auxiliary electrode 3 is connected with the output end of the operational amplifier, so that most of current passes through the auxiliary electrode 3, almost no current flows through the reference electrode 2, namely no electrons pass through the reference electrode, and the reaction AgCl + e is weakened - →Ag+Cl - The life of the reference electrode 2 is extended.
Example 3: the first conductive substrate 11 is made of stainless steel, the first metal transition layer 12 is made of gold, the first noble metal layer 13 is made of platinum, the inner coupling layer 14 and the outer coupling layer 16 are made of silane, the immobilized enzyme layer 15 is made of glucose oxidase, and the first polymer film layer 17 is made of polyurethane and/or polyethylene glycol.
The first conductive substrate 11 is preferably made of 304 stainless steel or 316 stainless steel, so that the toughness is good, the human rejection reaction is small, and the safety is high; the immobilized enzyme layer 15 is glucose oxidase which can effectively catalyze glucose + O 2 → gluconic acid + H 2 O 2 The reaction occurs, the first polymer film layer 17 is polyurethane and/or polyethylene glycol, which can limit glucose from entering the immobilized enzyme layer 15 to participate in the reaction, and ensure that enough oxygen participates in the reaction, so that the glucose concentration is H 2 O 2 A factor determining the amount of production; the first metal transition layer 12 is made of gold, and the first noble metal layer 13 is made of platinum, which can effectively catalyze H 2 O 2 →O 2 +2H + +2e - Reaction takes place with H 2 O 2 The generated quantity is converted into electron generated quantity, electrons generate micro current through the working electrode 1, and the gold and the platinum can reduce the signal to noise ratio, so that the micro current and the glucose concentration are in a linear positive correlation; the inner coupling layer 14 and the outer coupling layer 16 are preferably made of silane, which not only can achieve a good coupling effect and improve the stability of the immobilized enzyme layer 15, but also simplifies the process, so that the quality of the working electrode 1 can be controlled.
The second conductive substrate 21 is made of stainless steel, the second metal transition layer 22 is made of silver, and the second polymer film layer 24 is made of polyurethane and/or polyethylene glycol.
The second conductive substrate 21 is preferably made of 304 stainless steel or 316 stainless steel, so that the toughness is good, the human rejection reaction is small, and the safety is high; the second metal transition layer 22 is silver and the transition silver/silver chloride layer 23 outside the silver layer has high accuracy and stability.
The third conductive substrate 31 is made of stainless steel, the third metal transition layer 32 is made of gold, the second noble metal layer 33 is made of platinum, the coupling layer 34 is made of silane, and the third polymer film layer 35 is made of polyurethane and/or polyethylene glycol.
The third conductive substrate 31 is preferably made of 304 stainless steel or 316 stainless steel, so that the toughness is good, the human rejection reaction is small, and the safety is high; the third metal transition layer 32 is made of gold, and the second noble metal layer 33 is made of platinum, so that the current signal-to-noise ratio can be reduced, and the current stability after a loop is formed with the working electrode 1 is ensured.
Two sensors, one of which was a three-electrode sensor and the other of which was a two-electrode sensor with the auxiliary electrode removed, were fabricated according to the structure of example 3, and subjected to amperometric testing in glucose solution of phosphate buffered saline in vitro, with the following results:
table 1: three-electrode sensor in-vitro test current and linear correlation
Table 2: in-vitro test current and linear correlation degree of double-electrode sensor
The linear correlation represents the correlation between the current value change of the sensor and the concentration change of the test solution, the closer to 100 percent, the better the performance of the sensor is, and as can be seen from the comparison between table 1 and table 2, the linear correlation of the three-electrode sensor is still more than 99.9 percent when the test is carried out on day 18, the attenuation of the linear correlation of the two-electrode sensor begins to appear when the test is carried out on day 7, and the attenuation is obvious when the test is carried out on day 9, so the test is not carried out any more.
As shown in fig. 7, which is a comparison of the line graphs of the linear correlation of the three-electrode sensor and the two-electrode sensor, it can be seen that the three-electrode sensor can maintain better accuracy up to 18 days, and the stability of the two-electrode sensor decreases significantly up to 6 days.
The change in the sensor is also evident from the photograph after three days of operation, as in fig. 8, where the reference electrode of the three-electrode sensor is only partially whitish in the needle, whereas the reference electrode of the two-electrode sensor is already substantially completely whitish.
Example 4: the manufacturing method for manufacturing the three-electrode subcutaneously implanted glucose sensor in the embodiment comprises the steps that the sensor comprises a needle-shaped working electrode 1, a reference electrode 2 and an auxiliary electrode 3, wherein the working electrode 1, the reference electrode 2 and the auxiliary electrode 3 are fixed on a sensor seat 4;
the working electrode 1 comprises a first conductive substrate 11, a first metal transition layer 12, a first noble metal layer 13, an inner coupling layer 14, an immobilized enzyme layer 15, an outer coupling layer 16 and a first polymer film layer 17 from inside to outside, wherein the first conductive substrate 11 is made of stainless steel, the first metal transition layer 12 is made of gold, the first noble metal layer 13 is made of platinum, the inner coupling layer 14 and the outer coupling layer 16 are made of silane, the immobilized enzyme layer 15 is glucose oxidase, and the first polymer film layer 17 is made of polyurethane and/or polyethylene glycol;
the reference electrode 2 comprises a second conductive substrate 21, a second metal transition layer 22, a silver/silver chloride layer 23 and a second polymer film layer 24 from inside to outside, wherein the second conductive substrate 21 is made of stainless steel, the second metal transition layer 22 is made of silver, and the second polymer film layer 24 is made of polyurethane and/or polyethylene glycol;
the auxiliary electrode 3 comprises a third conductive substrate 31, a third metal transition layer 32, a second noble metal layer 33, a coupling layer 34 and a third high molecular film layer 35 from inside to outside, wherein the third conductive substrate 31 is made of stainless steel, the third metal transition layer 32 is made of gold, the second noble metal layer 33 is made of platinum, the coupling layer 34 is made of silane, and the third high molecular film layer 35 is made of polyurethane and/or polyethylene glycol;
a first metal transition layer 12 of the working electrode 1 is covered on the outer layer of the first conductive matrix 11 by adopting a cation etching method; the first noble metal layer 13 is covered on the outer layer of the first metal transition layer 12 by adopting a cation etching method or an electrochemical deposition method; the inner coupling layer 14 is covered on the outer layer of the first noble metal layer 13 in a dipping or coating mode; the immobilized enzyme layer 15 is attached to the outer layer of the inner coupling layer 14 by an enzyme solution in a dipping or coating mode; the outer coupling layer 16 is covered on the outer layer of the immobilized enzyme layer 15 in a dipping or coating mode; the first polymer film layer 17 is coated on the outer layer of the outer coupling layer 16 by adopting a dipping or coating mode.
The working electrode 1 is characterized in that a gold layer is electroplated on the outer layer of the stainless steel needle, a platinum layer is deposited on the outer layer of the gold layer through a cation etching method or an electrochemical method, silane is impregnated or coated on the outer layer of the platinum layer, glucose oxidase is impregnated or coated on the outer layer, silane is impregnated or coated on the outer layer of the enzyme layer, and finally polyurethane and/or polyethylene glycol are impregnated or coated on the outer layer of the enzyme layer.
The second metal transition layer 22 of the reference electrode 2 covers the outer layer of the second conductive matrix 21 by adopting a cation etching method; the silver/silver chloride layer 23 is formed by chlorination of the second metal transition layer 22; the second polymer film layer 24 is coated on the outer layer of the silver/silver chloride layer 23 by adopting a dipping or coating mode.
The reference electrode 2 is used for plating a silver layer on the outer layer of the stainless steel needle, chloridizing the silver layer to generate a silver/silver chloride layer, and then dipping or coating polyurethane and/or polyethylene glycol outside the silver/silver chloride layer.
The third metal transition layer 32 of the auxiliary electrode 3 covers the outer layer of the third conductive matrix 31 by adopting a cation etching method; the second noble metal layer 33 is covered on the outer layer of the third metal transition layer 32 by adopting a cation etching method or an electrochemical deposition method; the coupling layer 34 is covered on the outer layer of the second noble metal layer 33 in a dipping or coating mode; the third polymer film layer 35 is coated on the outer layer of the coupling layer 34 by dipping or coating.
The auxiliary electrode 3 is equivalent to the working electrode 1, the glucose oxidase layer is removed, other structures and manufacturing methods are the same as those of the working electrode, and the stability of current after the auxiliary electrode and the working electrode 1 form a loop is guaranteed.
Example 5: the method for fabricating the three-electrode is as in example 4, wherein the working electrode 1 is immobilized with the enzyme layer 15 by the following specific crosslinking method.
The solute of the enzyme solution is glucose oxidase, the solution is phosphoric acid buffer solution, and the concentration of the glucose oxidase is 0.02 g/ml-0.2 g/ml.
The glucose oxidase has better activity under the condition that the concentration of the glucose oxidase in the phosphoric acid buffer solution is 0.02-0.2 g/ml, and has better effect on the blood sugar catalytic reaction of a human body.
The glucose oxidase is cross-linked and solidified by glutaraldehyde.
Mixing glutaraldehyde and glucose oxidase solution in a certain proportion, covering the silane layer by adopting a dipping or coating mode, and dipping or coating the silane layer on the outer layer; free glucose oxidase is coupled through double functions of glutaraldehyde and silane, a sandwich layer similar to a sandwich is formed through crosslinking and curing, and free enzyme is combined into an aggregate, so that active sites of the enzyme are denser, the stability is high, and the stable and durable reaction capability is realized in continuous glucose monitoring.
The cross-linking temperature of the glucose oxidase and the glutaraldehyde is 25-35 ℃, and the single cross-linking time is 2-60min.
The glucose oxidase and the glutaraldehyde are crosslinked for 2 min to 60min at the temperature of 25 ℃ to 35 ℃, so that the enzyme activity is stable, the aggregation is better, and the effect of the human blood glucose catalytic reaction is ensured.
The times of dipping or coating the glucose oxidase and the glutaraldehyde on the working electrode 1 are not less than 3 times.
Through repeated dipping or coating, the distribution of the glucose oxidase on the working electrode 1 is more uniform, the thickness of the immobilized enzyme layer 15 is thicker, the continuous glucose monitoring of the human body is more stable and durable, and the service life of the working electrode 1 is prolonged.
Under the condition that the temperature is 25 ℃, enzyme solutions with different concentrations are subjected to cross-linking for different times (the time of single cross-linking is 30 min), and then sensitivity in vitro tests are carried out by using three-electrode sensors made of different working electrodes 1, so that the following test data are obtained:
table 3: the sensitivity (nA/mmol) of the sensor is obtained after different times of coating enzyme solutions with different concentrations
The sensitivity of the sensor can ensure that the monitoring of the blood sugar value is more accurate when the sensitivity of the sensor is more than 10 nA/mmol, and the test data shows that the sensitivity of the three-electrode sensor can meet the requirement when the concentration of glucose oxidase in an enzyme solution exceeds 0.02g/ml and the dipping or coating times of the glucose oxidase and glutaraldehyde after mixing are not less than 3 times, and the sensitivity of the sensor even reaches more than 60nA/mmol when the concentration of the glucose oxidase in the enzyme solution exceeds 0.2g/ml, and the sensitivity is no longer a main factor influencing the performance of the sensor when the sensitivity reaches more than 60 nA/mmol; in addition, as can be seen from current data obtained by a user wearing the sensor, when the enzyme solution is subjected to single crosslinking, the sensitivity of the sensor greatly fluctuates along with the wearing time; comprehensively considering the problems of cost, efficiency, sensor stability and the like, generally controlling the concentration of the glucose oxidase in the phosphoric acid buffer solution to be 0.02-0.08 g/ml, and dipping or coating the mixed solution of the glucose oxidase and glutaraldehyde on the working electrode 1 for 5 times; when the concentration of the glucose oxidase in the phosphoric acid buffer solution is 0.08-0.14 g/ml, dipping or coating the mixed solution of the glucose oxidase and glutaraldehyde on the working electrode 1 for 4 times; when the concentration of the glucose oxidase in the phosphate buffer solution is 0.14 g/ml-0.2 g/ml, the mixed solution of the glucose oxidase and the glutaraldehyde is dipped or coated on the working electrode 1 for 3 times.
The above-described embodiments are merely illustrative of the preferred embodiments of the present invention and do not limit the spirit and scope of the present invention. Various modifications and improvements of the technical solutions of the present invention may be made by those skilled in the art without departing from the design concept of the present invention, and the technical contents of the present invention are all described in the claims.
Claims (10)
1. A three-electrode subcutaneously implantable glucose sensor, comprising: the device comprises a needle-shaped working electrode (1), a reference electrode (2) and an auxiliary electrode (3), wherein the working electrode (1), the reference electrode (2) and the auxiliary electrode (3) are fixed on a sensor seat (4); the working electrode (1) comprises a first conductive substrate (11), a first metal transition layer (12), a first noble metal layer (13), an inner coupling layer (14), an immobilized enzyme layer (15), an outer coupling layer (16) and a first polymer film layer (17) from inside to outside;
the reference electrode (2) comprises a second conductive substrate (21), a second metal transition layer (22), a silver \ silver chloride layer (23) and a second polymer film layer (24) from inside to outside;
the auxiliary electrode (3) comprises a third conductive substrate (31), a third metal transition layer (32), a second noble metal layer (33), a coupling layer (34) and a third high molecular film layer (35) from inside to outside;
the first conductive substrate (11) is made of stainless steel, the first metal transition layer (12) is made of gold, the first precious metal layer (13) is made of platinum, the inner coupling layer (14) and the outer coupling layer (16) are made of silane, the immobilized enzyme layer (15) is made of glucose oxidase, and the first polymer membrane layer (17) is made of polyurethane and/or polyethylene glycol;
the third conductive substrate (31) is made of stainless steel, the third metal transition layer (32) is made of gold, the second noble metal layer (33) is made of platinum, the coupling layer (34) is made of silane, and the third polymer film layer (35) is made of polyurethane and/or polyethylene glycol;
an operational amplifier is installed in the transmitter, the reference electrode is connected with the reverse input end of the operational amplifier, and the auxiliary electrode is connected with the output end of the operational amplifier.
2. The three-electrode subcutaneously implantable glucose sensor of claim 1, wherein: the sensor seat (4) comprises a plastic base body (41), three metal connection points (42) which are arranged in a triangular mode are located in the middle of the plastic base body (41), a mounting hole is formed in the middle of each metal connection point (42), and the needle tail ends of the working electrode (1), the reference electrode (2) and the auxiliary electrode (3) penetrate through the mounting holes respectively and then are connected and conducted with the metal connection points (42).
3. The three-electrode subcutaneously implantable glucose sensor of claim 2, wherein: the three metal connecting points (42) are arranged in a regular triangle, and the side length of the regular triangle is 3-6 mm.
4. A three-electrode subcutaneously implantable glucose sensor according to claim 3, wherein: the working electrode (1), the reference electrode (2) and the auxiliary electrode (3) are all arranged perpendicular to the plastic substrate (41).
5. The three-electrode subcutaneously implantable glucose sensor of claim 2, wherein: the sensor seat (4) further comprises at least three metal contacts (43) positioned on the plastic base body (41), the metal contacts (43) are respectively communicated with the metal connecting points (42), and the plastic base body (41) is provided with a clamping mechanism (411) connected with the emitter.
6. The three-electrode subcutaneously implantable glucose sensor of claim 5, wherein: an operational amplifier is installed in the transmitter, the reference electrode (2) is electrically connected with the reverse input end of the operational amplifier through the metal connecting point (42) and the metal contact (43), and the auxiliary electrode (3) is electrically connected with the output end of the operational amplifier through the metal connecting point (42) and the metal contact (43).
7. The three-electrode subcutaneously implantable glucose sensor of claim 1, wherein: the second conductive substrate (21) is made of stainless steel, the second metal transition layer (22) is made of silver, and the second polymer film layer (24) is made of polyurethane and/or polyethylene glycol.
8. A manufacturing method of a three-electrode subcutaneous implantation type glucose sensor is characterized by comprising the following steps: the sensor comprises a needle-shaped working electrode (1), a reference electrode (2) and an auxiliary electrode (3), wherein the working electrode (1), the reference electrode (2) and the auxiliary electrode (3) are fixed on a sensor seat (4);
the working electrode (1) comprises a first conductive substrate (11), a first metal transition layer (12), a first noble metal layer (13), an inner coupling layer (14), an immobilized enzyme layer (15), an outer coupling layer (16) and a first high polymer film layer (17) from inside to outside, wherein the first conductive substrate (11) is made of stainless steel, the first metal transition layer (12) is gold, the first noble metal layer (13) is platinum, the inner coupling layer (14) and the outer coupling layer (16) are made of silane, the immobilized enzyme layer (15) is glucose oxidase, and the first high polymer film layer (17) is made of polyurethane and/or polyethylene glycol;
the reference electrode (2) comprises a second conductive substrate (21), a second metal transition layer (22), a silver/silver chloride layer (23) and a second polymer film layer (24) from inside to outside, wherein the second conductive substrate (21) is made of stainless steel, the second metal transition layer (22) is made of silver, and the second polymer film layer (24) is made of polyurethane and/or polyethylene glycol;
the auxiliary electrode (3) comprises a third conductive substrate (31), a third metal transition layer (32), a second noble metal layer (33), a coupling layer (34) and a third high molecular film layer (35) from inside to outside, wherein the third conductive substrate (31) is made of stainless steel, the third metal transition layer (32) is made of gold, the second noble metal layer (33) is made of platinum, the coupling layer (34) is made of silane, and the third high molecular film layer (35) is made of polyurethane and/or polyethylene glycol;
the first metal transition layer (12) of the working electrode (1) is plated on the outer layer of the first conductive base body (11) by adopting an electroplating method; the first noble metal layer (13) is covered on the outer layer of the first metal transition layer (12) by adopting a cation etching method or an electrochemical deposition method; the inner coupling layer (14) is covered on the outer layer of the first noble metal layer (13) in a dipping or coating mode; the immobilized enzyme layer (15) is attached to the outer layer of the inner coupling layer (14) by an enzyme solution in a dipping or coating mode; the outer coupling layer (16) is covered on the outer layer of the immobilized enzyme layer (15) in a dipping or coating mode; the first polymer film layer (17) is covered on the outer layer of the outer coupling layer (16) in a dipping or coating mode;
the solute of the enzyme solution is glucose oxidase, the solution is phosphoric acid buffer solution, and the concentration of the glucose oxidase is 0.06 g/ml-0.12 g/ml; the glucose oxidase is cross-linked and cured by glutaraldehyde, the cross-linking temperature of the glucose oxidase and the glutaraldehyde is 25-35 ℃, and the single cross-linking time is 20-60 min;
the times of dipping or coating the glucose oxidase and the glutaraldehyde on the working electrode (1) are not less than 3.
9. The method for manufacturing a three-electrode subcutaneously implantable glucose sensor according to claim 8, wherein: the second metal transition layer (22) of the reference electrode (2) is plated on the outer layer of the second conductive base body (21) by adopting an electroplating method; the silver/silver chloride layer (23) is formed by chlorination of the second metal transition layer (22); the second polymer film layer (24) is covered on the outer layer of the silver/silver chloride layer (23) in a dipping or coating mode.
10. The method for manufacturing a three-electrode subcutaneously implantable glucose sensor according to claim 8, wherein: the third metal transition layer (32) of the auxiliary electrode (3) is plated on the outer layer of the third conductive base body (31) by adopting an electroplating method; the second noble metal layer (33) is covered on the outer layer of the third metal transition layer (32) by adopting a cation etching method or an electrochemical deposition method; the coupling layer (34) is covered on the outer layer of the second noble metal layer (33) in a dipping or coating mode; the third high molecular film layer (35) is covered on the outer layer of the coupling layer (34) in a dipping or coating mode.
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